MDMA is a popular recreational drug that damages serotonergic nerve terminals in the brain of rodent as well as non-human primates. Whether the damage is reversible or permanent is currently unknown, but this is an important question given recent preliminary findings indicating that humans who use MDMA may incur central serotonergic neuronal damage. The purpose of this research is to characterize the long-term effects of MDMA on serotonergic neurons in the b#in of non-human primates, and to define factors that determine whether the toxic effects of MDMA are reversible or permanent. The first set of studies will examine the potential for neuronal recovery in MDMA-treated monkeys that have sustained severe serotonergic nerve fiber damage, but no cell body loss in the raphe nuclei. Pilot studies indicate that partial recovery of serotonin takes place in these animals over a ten week period. This finding will be confirmed and extended by (1) measuring other chemical markers for serotonergic fibers (serotonin uptake sites and 5- hydroxyindoleacetic acid concentrations), (2) establishing the time-course and extent of recovery in various brain regions, (3) determining whether neurochemical recovery is related to regeneration of serotonergic nerve fibers and (4) investigating if the distribution and appearance of the regenerated fibers is normal. Results from these studies should yield information regarding the long-term effects of MDMA on central serotonergic neurons in non-human primates, and could prove directly relevant to humans who have sustained MDMA-induced neuronal damage. A second set of studies will attempt to identify conditions under which MDMA produces permanent toxic effects on central serotonergic neurons in the primate. In particular, it will be examined if higher or more protected dosage regimens of MDMA lead to destruction of serotonergic nerve cell bodies in the raphe nuclei. Under such conditions, irreversible effects would, of course, be anticipated. Identification of a dosage regimen of MDMA that produces extensive destruction of serotonergic nerve cell bodies could have several useful applications. MDMA-treated monkeys with a large and permanent depletion of brain serotonin could be used to define the functional role of serotonergic neurons in the primate brain. Studies in such animals could also provide valuable guidance for the clinical assessment of humans who show biochemical evidence of MDMA-induced serotonergic neuronal damage. The finding that higher or more protracted doses of MDMA produce irreversible effects on serotonergic neurons would also have important implications for those humans who use repeated high doses of this drug. The long-term objectives of this research are to further define the functional role of serotonergic neurons in the primate brain and to characterize the long-term consequences of MDMA intoxication in human and non-human primates.